From risk communication about asymptomatic atherosclerosis to cognitive and emotional reactions and lifestyle modification.

BACKGROUND: Non-adherence in the general population to preventive guidelines on cardiovascular disease calls for an interdisciplinary approach acknowledging psychological factors of relevance for risk communication and lifestyle modification. Evidence is building up regarding the advantage of sharing arterial imaging evidence of subclinical atherosclerosis with asymptomatic individuals, but there is limited understanding of how this relates to mechanisms of importance for behavioural change. Longitudinal studies on associations between patients' reactions and lifestyle modification are missing. The population-based randomized controlled trial VIPVIZA investigates the impact of pictorial information about subclinical atherosclerosis, added to traditional risk factor-based communication. The intervention includes a personalized, colour-coded and age-related risk communication strategy and a motivational conversation, and has been shown to reduce cardiovascular disease risk. METHODS: In the present study we assessed cognitive and emotional reactions to the intervention, and how these reactions are associated to lifestyle modification. The participants' evaluation of the risk communication was assessed in the intervention group (n = 1749). Lifestyle modification was assessed with a lifestyle index based on physical activity, diet, smoking and alcohol consumption at baseline and after 3 years. Associations between cognitive and emotional response and lifestyle modification were tested with analyses of covariance in a subset of participants (n = 714-857). RESULTS: The intervention increased understanding of personal CVD risk, the possibility to influence the risk, and how to influence the risk. Severity of atherosclerosis was associated with emotional reactions, but emotions of strong negative valence were uncommon. Cognitive response and emotional arousal evoked by the intervention were positively associated with lifestyle modification, whereas negative emotions in isolation were not. High level of cognitive response in combination with high level of emotional arousal was found to be most beneficial for lifestyle modification. CONCLUSIONS: The results demonstrate the potential of communicating asymptomatic atherosclerosis with a pictorial, colour-coded and age-related strategy, also including a motivational conversation. Furthermore, the results show the importance of CVD risk communication evoking engagement, and that an interaction between cognitive and emotional reactions might be central for sustained lifestyle modification. Our results also indicate that, in an asymptomatic population, atherosclerosis screening may strengthen disease prevention and health promotion. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01849575. Registration date 08/05/2013.

Does a multi-component intervention including pictorial risk communication about subclinical atherosclerosis improve perceptions of cardiovascular disease risk without deteriorating efficacy beliefs?

BACKGROUND: Pictorial communication about subclinical atherosclerosis can improve cardiovascular disease (CVD) risk, but whether it leads to long-term shifts in self-rated CVD risk (risk perception) and beliefs about possibility to influence personal risk (efficacy beliefs) is unknown. PURPOSE: To study the impact of personalized color-coded and age-related risk communication about atherosclerosis and motivational conversation, compared to traditional risk factor-based communication, on risk perception and efficacy beliefs. Also, whether risk perception increases with message severity. METHOD: The effect of the pragmatic RCT Visualization of Asymptomatic Atherosclerotic Disease for Optimum Cardiovascular Prevention (VIPVIZA) was analyzed using a linear mixed effects model with risk perception and efficacy believes at 1-year and 3-year follow up as dependent variables. Participants' (n = 3532) CVD risk perception and efficacy beliefs were assessed with visual analog scales (0-10). Fixed effects were group (intervention vs control), time point (1 year or 3 years) and interaction between group and time point. Further, the models were adjusted for corresponding baseline measurement of the dependent variable and a baseline × time point interaction. Effect of pictorial color-coded risk in the intervention group was investigated using a corresponding mixed effects model, but with pictorial risk group (message severity) as exposure instead of intervention group. RESULTS: After one year, the intervention group rated their CVD risk as higher (m = 0.46, 95% CI 0.32-0.59), with an effect also after 3 years (m = 0.57, 95% CI 0.43-0.70). The effect was consistent in stratified analyses by sex and education. Overall, no effect on efficacy beliefs was observed. In the intervention group, differences in CVD risk perception were found between participants with different color-coded risk messages on atherosclerosis status. CONCLUSION: Personalized, color-coded and age-related risk communication about atherosclerosis had an effect on risk perception with an effect also after 3 years, whereas overall, no effect on efficacy beliefs was observed.

Quantification of chondroitin sulfate, hyaluronic acid and N-glycans in synovial fluid - A technical performance study.

Objective: To validate a quantitative high performance liquid chromatography (HPLC) assay for chondroitin sulfate (CS) and hyaluronic acid (HA) in synovial fluid, and to analyze glycan-patterns in patient samples. Design: Synovial fluid from osteoarthritis (OA, n â€‹= â€‹25) and knee-injury (n â€‹= â€‹13) patients, a synovial fluid pool (SF-control) and purified aggrecan, were chondroitinase digested and together with CS- and HA-standards fluorophore labelled prior to quantitative HPLC analysis. N-glycan profiles of synovial fluid and aggrecan were assessed by mass spectrometry. Results: Unsaturated uronic acid and sulfated-N-acetylgalactosamine (ΔUA-GalNAc4S and ΔUA-GalNAc6S) contributed to 95% of the total CS-signal in the SF-control sample. For HA and the CS variants in SF-control the intra- and inter-experiment coefficient of variation was between 3-12% and 11-19%, respectively; tenfold dilution gave recoveries between 74 and 122%, and biofluid stability test (room temperature storage and freeze-thaw cycles) showed recoveries between 81 and 140%. Synovial fluid concentrations of the CS variants ΔUA-GalNAc6S and ΔUA2S-GalNAc6S were three times higher in the recent injury group compared to the OA group, while HA was four times lower. Sixty-one different N-glycans were detected in the synovial fluid samples, but there were no differences in levels of N-glycan classes between patient groups. The CS-profile (levels of ΔUA-GalNAc4S and ΔUA-GalNAc6S) in synovial fluid resembled that of purified aggrecan from corresponding samples; the contribution to the N-glycan profile in synovial fluid from aggrecan was low. Conclusions: The HPLC-assay is suitable for analyzing CS variants and HA in synovial fluid samples, and the GAG-pattern differs between OA and recently knee injured subjects.

Navigating cultural transitions during resettlement: the case of unaccompanied refugee minors.

Introduction: Refugees face the process of cross-cultural transitions upon arrival in their host country. This process is commonly referred to as acculturation and can be particularly challenging for asylum-seeking children and adolescent unaccompanied by a caregiver. To more effectively facilitate unaccompanied refugee minors (URMs) resettlement, this study sought to obtain an enhanced understanding of the acculturation processes of these youth'. Methods: Thus, interviews with 48 URMs, all of whom arrived before the age of 16 years, were analyzed in two steps. First, how the youth described their host country's society and culture, followed by how they navigated within this societal and cultural landscape during resettlement. Results: The youth described how they navigated the Norwegian cultural and societal landscape by gaining cultural competence, adapting and finding ways to contribute, which made it easier for the youth to gain access to the society, to succeed as well as enhance their sense of agency. However, the youths also reported having to navigate between the expectations of their original and host country cultures, struggling with finding a balance between the two cultures. Discussion: The youth' acculturation processes seemed to be the result of both their own needs, wishes and behavior as well as specific features in their host country culture, which supports the notion that acculturation processes to some degree are context- and culture-dependent. Knowledge regarding the cultural and societal framework that these youth face and how they navigate within it during resettlement is critical for identifying possible cross-cultural challenges and promoting positive developmental tracks. To understand more about acculturation and integration processes, future research should include specific cultural and societal features as well as immigrants' own perspectives and experiences during resettlement.

Cognitive and emotional reactions to pictorial-based risk communication on subclinical atherosclerosis: a qualitative study within the VIPVIZA trial.

OBJECTIVES, SETTING AND SUBJECTS: Atherosclerosis screening with ultrasound is non-invasive and can be used as part of risk communication. The potential of personalised and pictorial-based risk communication is assessed in VIPVIZA, a population-based randomised controlled trial that aims at optimising cardiovascular disease (CVD) prevention by investigating the impact of visualisation of subclinical atherosclerosis. The present aim was to explore cognitive and emotional reactions evoked by the intervention as well as attitudes to any implemented life style changes in VIPVIZA participants in the intervention group with improved health status and furthermore to study possible interactions between these factors. Understanding mechanisms of action was central since non-adherence to preventive guidelines are often faced in clinical practice. DESIGN: In-depth interviews with 14 individuals were analysed with qualitative content analysis. RESULTS: Cognitive and emotional processes were highly interlinked and described by the main theme Cognitive and emotional reactions in strong interplay for orchestration of health oriented behavioural change. The informants' descriptions revealed two distinctly different psychological processes which constituted the two subthemes, Problem-focused coping and Encouragement-driven process. CONCLUSIONS: The results highlight that an interaction between emotional reactions and efficacy beliefs is important in facilitating behavioural change. Furthermore, the results underscore the importance of the risk message being perceived as clear, accurate, reliable and also emotionally engaging and thereby show why atherosclerosis screening and pictorial-based risk communication have the potential to contribute to effective CVD prevention strategies and shared decision making in primary care. Trial registration: ClinicalTrials.gov identifier: NCT01849575, registration 8 May 2013.Key pointsAtherosclerosis screening and pictorial-based risk communication have the potential to contribute to more effective CVD prevention strategies.Risk messages on atherosclerosis status were perceived as clear, accurate, reliable and emotionally engaging.An interplay between efficacy beliefs and emotional reactions facilitated behavioural change.Patients' understanding of CVD risk is important for shared decision-making and of relevance for non-adherence to preventive guidelines.

Reactions for actions? Trust in protective behaviors and safeguarding measures in the early phase of the Covid-19 pandemic in Sweden.

To minimize the spread of Covid-19, changing every-day behavior has been key. Trust in the effectiveness of individual protective measures (response efficacy) and confidence in collective safeguarding measures (strategy efficacy), offers an incitement for acting adequately. Efficacy beliefs of protective measures might be especially relevant to study in the Swedish context, since Sweden, in contrast to countries facing hard lock-downs, launched safeguarding measures based on individual responsibility and voluntary actions. We aimed to assess associations between on the one hand, response efficacy and strategy efficacy, and on the other hand, propensity for behavior change and support of protective measures. Furthermore, to assess associations between the efficacy beliefs and comprehension of and confidence in information about the virus, prosocial beliefs and worry of Covid-19. Reactions were assessed in a Swedish sample close in time to experiences via the SEMA3 app from March 25th to May 17th 2020. Study participants had replied to questions on strategy efficacy (n = 175) or response efficacy (n = 157) and 146 participants had replied to both. High response efficacy was associated with propensity for behavior change, support of protective measures and confidence in Covid-19 information. Low strategy efficacy was associated with lower comprehension of and confidence in information about Covid-19. The results suggest that strengthening efficacy beliefs can be a way to promote protective behaviors. Furthermore, the result underscores the importance of information being easy to understand and trustworthy. Finding ways to increase public understanding of the effectiveness of protective measures, including vaccination, seems crucial in pandemic times.

Using Ecological Momentary Assessment to Study the Development of COVID-19 Worries in Sweden: Longitudinal Study.

BACKGROUND: The foray of COVID-19 around the globe has certainly instigated worries in many people, and lockdown measures may well have triggered more specific worries. Sweden, more than other countries, relied on voluntary measures to fight the pandemic. This provides a particularly interesting context to assess people's reactions to the threat of the pandemic. OBJECTIVE: The general aim of this study was to better understand the worried reactions to the virus and the associated lockdown measures. As there have been very few longitudinal studies in this area published to date, development of feelings of worry over time was analyzed over a longer range than in previous research. Affective variables, worry in particular, were included because most of the research in this field has focused on cognitive variables. To employ new methodology, ecological momentary assessment was used for data collection and a multilevel modeling approach was adopted for data analysis. METHODS: Results were based on an unbalanced panel sample of 260 Swedish participants filling in 3226 interview questionnaires by smartphone over a 7-week period in 2020 during the rapid rise of cases in the early phase of the pandemic. Causal factors considered in this study included the perceived severity of an infection, susceptibility of a person to the threat posed by the virus, perceived efficacy of safeguarding measures, and assessment of government action against the spread of COVID-19. The effect of these factors on worries was traced in two analytical steps: the effects at the beginning of the study and the effect on the trend during the study. RESULTS: The level of general worry related to COVID-19 was modest (mean 6.67, SD 2.54 on an 11-point Likert scale); the increase during the study period was small, but the interindividual variation of both the worry level and its increase over time was large. Findings confirmed that the hypothesized causal factors (severity of infection, susceptibility to the threat of the virus, efficacy of safeguarding, and assessment of government preventive action) did indeed affect the level of worry. CONCLUSIONS: The results confirmed earlier research in a very special case and demonstrated the usefulness of a different study design, which takes a longitudinal perspective, and a new type of data analysis borrowed from multilevel study design.

A database of high-density surface electromyogram signals comprising 65 isometric hand gestures.

Control of contemporary, multi-joint prosthetic hands is commonly realized by using electromyographic signals from the muscles remaining after amputation at the forearm level. Although this principle is trying to imitate the natural control structure where muscles control the joints of the hand, in practice, myoelectric control provides only basic hand functions to an amputee using a dexterous prosthesis. This study aims to provide an annotated database of high-density surface electromyographic signals to aid the efforts of designing robust and versatile electromyographic control interfaces for prosthetic hands. The electromyographic signals were recorded using 128 channels within two electrode grids positioned on the forearms of 20 able-bodied volunteers. The participants performed 65 different hand gestures in an isometric manner. The hand movements were strictly timed using an automated recording protocol which also synchronously recorded the electromyographic signals and hand joint forces. To assess the quality of the recorded signals several quantitative assessments were performed, such as frequency content analysis, channel crosstalk, and the detection of poor skin-electrode contacts.

Clinicopathological concordance in cognitive disease diagnostics.

Neurocognitive disorder encompasses many separate diagnoses, such as frontotemporal dementia (FTD), Alzheimer's disease (AD), Lewy body dementia (LBD), vascular dementia (VaD), and mixed dementia (MD). Because of the many variations between and within each subtype, it may be a challenge to clinically diagnose each condition. In a previous study on 176 dementia patients in a university hospital cohort between the years 1996 and 2006, a full diagnostic concordance of 49% was demonstrated between clinical diagnoses and pathological morphology [1]. The aims of this study were to do a follow-up on diagnostic concordance from the subsequent 10 years (2007 - 2016) and to compare the results with the previous study from 2009. In all cases of neuropathologically diagnosed dementia disorders (n = 324), the clinical records were searched for information on the clinical diagnosis of dementia, including on subtype. All individuals who had been diagnosed by a specialist were selected (n = 210). In this study, a full concordance between clinical diagnoses and neuropathological morphology was found in 61% of individuals, with marked variations between subgroups, including the lowest (31%) in the group of VaD. Vigilance in clinicopathological concordance is important for quality maintenance as well as the improvement of skills in diagnostic work. In light of the previous study, VaD one decade later remains elusive. The unmasking of this complicated and multifaceted disorder may be beneficial to the overall diagnostic accuracy in cognitive disease investigations.
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Correction to: Long-term mental health in unaccompanied refugee minors: pre- and post-flight predictors.

In the original publication, the Table 1 was published.

Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study.

OBJECTIVE: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. METHODS: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. RESULTS: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. CONCLUSIONS: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.

Extraction of Multi-Labelled Movement Information from the Raw HD-sEMG Image with Time-Domain Depth.

In contemporary muscle-computer interfaces for upper limb prosthetics there is often a trade-off between control robustness and range of executable movements. As a very low movement error rate is necessary in practical applications, this often results in a quite severe limitation of controllability; a problem growing ever more salient as the mechanical sophistication of multifunctional myoelectric prostheses continues to improve. A possible remedy for this could come from the use of multi-label machine learning methods, where complex movements can be expressed as the superposition of several simpler movements. Here, we investigate this claim by applying a multi-labeled classification scheme in the form of a deep convolutional neural network (CNN) to high density surface electromyography (HD-sEMG) recordings. We use 16 independent labels to model the movements of the hand and forearm state, representing its major degrees of freedom. By training the neural network on 16 × 8 sEMG image sequences 24 samples long with a sampling rate of 2048 Hz to detect these labels, we achieved a mean exact match rate of 78.7% and a mean Hamming loss of 2.9% across 14 healthy test subjects. With this, we demonstrate the feasibility of highly versatile and responsive sEMG control interfaces without loss of accuracy.

Long-term mental health in unaccompanied refugee minors: pre- and post-flight predictors.

Unaccompanied refugee minors are a particularly vulnerable group. The aim of this study is to increase our knowledge about possible pathways to well-being and integration for unaccompanied refugee minors as they strive to establish new lives in a host county. The present study followed a group of youth who fled to Norway without their caregivers at three time points; 6 months (n = 95; M age = 13.8, 80% boys), 2 years (n = 78; M age = 16.5, 83% boys), and 5 years (n = 47; M age 20.0, 83% boys) after arrival. Linear mixed effects models were used to assess whether age, gender, and trauma exposure prior to arrival were associated with levels and changes in symptoms of posttraumatic stress (PTS), depression, anxiety, and externalizing symptoms over time. Regression analyses were conducted to examine whether daily hassles, perceived social support, and new trauma experiences predict PTS, internalization, externalization, and somatization. The mean levels of depression had decreased significantly at 5 years, but mean levels of anxiety, PTS, and externalizing symptoms did not. Females and severely trauma exposed had higher levels of symptoms. Higher age was associated with less change in symptoms of depression and posttraumatic stress over time. Five years after arrival, many still experienced clinical levels of mental health problems, and level of daily hassles was an important predictor. Support may be needed not only at arrival to handle mental health problems in general and posttraumatic stress in particular, but also after resettlement. Help to manage daily hassles may be especially important to ensure well-being and integration.

A Randomized Controlled Trial Comparing Er:YAG Laser and Rotary Bur in the Excavation of Caries - Patients' Experiences and the Quality of Composite Restoration.

OBJECTIVE: The aim of this study was to evaluate patients´ experiences of two excavation methods, Er:YAG laser and rotary bur and time required by the methods as well as objective assessments of quality and durability of restorations over a two-year period. METHODS: A prospective, single-blind, randomized and controlled investigation was performed. Patients aged 15 to 40 years with at least two primary caries lesions, which had been radiographically assessed as of the same size, were recruited. In each patient, one cavity was excavated using rotary bur and one using Er:YAG laser technique. The time required for excavations and, where applicable, local anaesthesia, was measured during the treatments. Patient experiences were measured using questionnaires. The quality and durability of restorations were assessed over a two-year period in accordance with modified Ryges criteria and radiographs. Twenty-five patients (mean age 22.6 years) participated in the study. In total, 56 cavities were included of which 28 were treated with Er:YAG laser and 28 were treated with a rotary bur. RESULTS: The patients associated the laser method with less discomfort. The mean time for excavation by laser was three times longer than by rotary bur (13.2 min vs. 4.3 min, P<0.0001). Over a two-year period, no statistically significant differences with regard to quality or durability could be seen between the restorations associated with the methods. CONCLUSION: The Er:YAG laser technique was more time-consuming than the rotary bur. Despite this, the laser technique caused less discomfort and was preferred as an excavation method by patients.

Prehospital Identification of Patients with a Final Hospital Diagnosis of Stroke.

Introduction the early phase of stroke, minutes are critical. Since the majority of patients with stroke are transported by the Emergency Medical Service (EMS), the early handling and decision making by the EMS clinician is important. Problem The study aim was to evaluate the frequency of a documented suspicion of stroke by the EMS nurse, and to investigate differences in the clinical signs of stroke and clinical assessment in the prehospital setting among patients with regard to if there was a documented suspicion of stroke on EMS arrival or not, in patients with a final hospital diagnosis of stroke. METHODS: The study had a retrospective observational design. Data were collected from reports on patients who were transported by the EMS and had a final diagnosis of stroke at a single hospital in western Sweden (630 beds) in 2015. The data sources were hospital and prehospital medical journals. RESULTS: In total, 454 patients were included. Among them, the EMS clinician suspected stroke in 52%. The findings and documentation on patients with a suspected stroke differed from the remaining patients as follows: a) More frequently documented symptoms from the face, legs/arms, and speech; b) More frequently assessments of neurology, face, arms/legs, speech, and eyes; c) More frequently addressed the major complaint with regard to time and place of onset, duration, localization, and radiation; d) Less frequently documented symptoms of headache, vertigo, and nausea; and e) More frequently had an electrocardiogram (ECG) recorded and plasma glucose sampled. In addition to the 52% of patients who had a documented initial suspicion of stroke, seven percent of the patients had an initial suspicion of transitory ischemic attack (TIA) by the EMS clinician, and a neurologist was approached in another 10%. CONCLUSION: Among 454 patients with a final diagnosis of stroke who were transported by the EMS, an initial suspicion of stroke was not documented in one-half of the cases. These patients differed from those in whom a suspicion of stroke was documented in terms of limited clinical signs of stroke, a less extensive clinical assessment, and fewer clinical investigations. Andersson E , Bohlin L , Herlitz J , Sundler AJ , Fekete Z , Andersson Hagiwara M . Prehospital identification of patients with a final hospital diagnosis of stroke. Prehosp Disaster Med. 2018;33(1):63-70.

High visual acuity revealed in dogs.

Humans have selectively bred and used dogs over a period of thousands of years, and more recently the dog has become an important model animal for studies in ethology, cognition and genetics. These broad interests warrant careful descriptions of the senses of dogs. Still there is little known about dog vision, especially what dogs can discriminate in different light conditions. We trained and tested whippets, pugs, and a Shetland sheepdog in a two-choice discrimination set-up and show that dogs can discriminate patterns with spatial frequencies between 5.5 and 19.5 cycle per degree (cpd) in the bright light condition (43 cd m-2). This is a higher spatial resolution than has been previously reported although the individual variation in our tests was large. Humans tested in the same set-up reached acuities corresponding to earlier studies, ranging between 32.1 and 44.2 cpd. In the dim light condition (0.0087 cd m-2) the acuity of dogs ranged between 1.8 and 3.5 cpd while in humans, between 5.9 and 9.9 cpd. Thus, humans make visual discrimination of objects from roughly a threefold distance compared to dogs in both bright and dim light.

An Implementation Research Approach to Evaluating Health Insurance Programs: Insights from India.

One of the distinguishing features of implementation research is the importance given to involve implementers in all aspects of research, and as users of research. We report on a recent implementation research effort in India, in which researchers worked together with program implementers from one of the longest serving government funded insurance schemes in India, the Rajiv Aarogyasri Scheme (RAS) in the state of undivided Andhra Pradesh, that covers around 70 million people. This paper aims to both inform on the process of the collaborative research, as well as, how the nature of questions that emerged out of the collaborative exercise differed in scope from those typically asked of insurance program evaluations. Starting in 2012, and over the course of a year, staff from the Aarogyasri Health Care Trust (AHCT), and researchers held a series of meetings to identify research questions that could serve as a guide for an evaluation of the RAS. The research questions were derived from the application of a Logical Framework Approach ("log frame") to the RAS. The types of questions that emerged from this collaborative effort were compared with those seen in the published literature on evaluations of insurance programs in low- and middle-income countries (LMICs). In the published literature, 60% of the questions pertained to output/outcome of the program and the remaining 40%, relate to processes and inputs. In contrast, questions generated from the RAS participatory research process between implementers and researchers had a remarkably different distribution - 81% of questions looked at program input/processes, and 19% on outputs and outcomes. An implementation research approach can lead to a substantively different emphasis of research questions. While there are several challenges in collaborative research between implementers and researchers, an implementation research approach can lead to incorporating tacit knowledge of program implementers into the research process, research questions that are more relevant to the research needs of policy-makers, and greater knowledge translation of the research findings.

Filtration Device for On-Site Collection, Storage and Shipment of Cells from Urine and Its Application to DNA-Based Detection of Bladder Cancer.

Molecular analysis of cells from urine provides a convenient approach to non-invasive detection of bladder cancer. The practical use of urinary cell-based tests is often hampered by difficulties in handling and analyzing large sample volumes, the need for rapid sample processing to avoid degradation of cellular content, and low sensitivity due to a high background of normal cells. We present a filtration device, designed for home or point-of-care use, which enables collection, storage and shipment of urinary cells. A special feature of this device is a removable cartridge housing a membrane filter, which after filtration of urine can be transferred to a storage unit containing an appropriate preserving solution. In spiking experiments, the use of this device provided efficient recovery of bladder cancer cells with elimination of >99% of excess smaller-sized cells. The performance of the device was further evaluated by DNA-based analysis of urinary cells collected from 57 patients subjected to transurethral resection following flexible cystoscopy indicating the presence of a tumor. All samples were tested for FGFR3 mutations and seven DNA methylation markers (BCL2, CCNA1, EOMES, HOXA9, POU4F2, SALL3 and VIM). In the group of patients where a transitional cell tumor was confirmed at histopathological evaluation, urine DNA was positive for one or more markers in 29 out of 31 cases (94%), including 19 with FGFR3 mutation (61%). In the group of patients with benign histopathology, urine DNA was positive for methylation markers in 13 out of 26 cases (50%). Only one patient in this group was positive for a FGFR3 mutation. This patient had a stage Ta tumor resected 6 months later. The ability to easily collect, store and ship diagnostic cells from urine using the presented device may facilitate non-invasive testing for bladder cancer.

DNA methylation and histone modifications regulate SOX11 expression in lymphoid and solid cancer cells.

BACKGROUND: The neural transcription factor SOX11 is present at specific stages during embryo development with a very restricted expression in adult tissue, indicating precise regulation of transcription. SOX11 is strongly up-regulated in some malignancies and have a functional role in tumorgenesis. With the aim to explore differences in epigenetic regulation of SOX11 expression in normal versus neoplastic cells, we investigated methylation and histone modifications related to the SOX11 promoter and the possibility to induce re-expression using histone deacetylase (HDAC) or EZH2 inhibitors. METHODS: The epigenetic regulation of SOX11 was investigated in distinct non-malignant cell populations (n = 7) and neoplastic cell-lines (n = 42) of different cellular origins. DNA methylation was assessed using bisulfite sequencing, methylation-specific melting curve analysis, MethyLight and pyrosequencing. The presence of H3K27me3 was assessed using ChIP-qPCR. The HDAC inhibitors Vorinostat and trichostatin A were used to induce SOX11 in cell lines with no endogenous expression. RESULTS: The SOX11 promoter shows a low degree of methylation and strong enrichment of H3K27me3 in non-malignant differentiated cells, independent of cellular origin. Cancers of the B-cell lineage are strongly marked by de novo methylation at the SOX11 promoter in SOX11 non-expressing cells, while solid cancer entities display a more varying degree of SOX11 promoter methylation. The silencing mark H3K27me3 was generally present at the SOX11 promoter in non-expressing cells, and an increased enrichment was observed in cancer cells with a low degree of SOX11 methylation compared to cells with dense methylation. Finally, we demonstrate that the HDAC inhibitors (vorinostat and trichostatin A) induce SOX11 expression in cancer cells with low levels of SOX11 methylation. CONCLUSIONS: We show that SOX11 is strongly marked by repressive histone marks in non-malignant cells. In contrast, SOX11 regulation in neoplastic tissues is more complex involving both DNA methylation and histone modifications. The possibility to re-express SOX11 in non-methylated tissue is of clinical relevance, and was successfully achieved in cell lines with low levels of SOX11 methylation. In breast cancer patients, methylation of the SOX11 promoter was shown to correlate with estrogen receptor status, suggesting that SOX11 may be functionally re-expressed during treatment with HDAC inhibitors in specific patient subgroups.

Size-based enrichment of exfoliated tumor cells in urine increases the sensitivity for DNA-based detection of bladder cancer.

Bladder cancer is diagnosed by cystoscopy, a costly and invasive procedure that is associated with patient discomfort. Analysis of tumor-specific markers in DNA from sediments of voided urine has the potential for non-invasive detection of bladder cancer; however, the sensitivity is limited by low fractions and small numbers of tumor cells exfoliated into the urine from low-grade tumors. The purpose of this study was to improve the sensitivity for non-invasive detection of bladder cancer by size-based capture and enrichment of tumor cells in urine. In a split-sample set-up, urine from a consecutive series of patients with primary or recurrent bladder tumors (N = 189) was processed by microfiltration using a membrane filter with a defined pore-size, and sedimentation by centrifugation, respectively. DNA from the samples was analyzed for seven bladder tumor-associated methylation markers using MethyLight and pyrosequencing assays. The fraction of tumor-derived DNA was higher in the filter samples than in the corresponding sediments for all markers (p<0.000001). Across all tumor stages, the number of cases positive for one or more markers was 87% in filter samples compared to 80% in the corresponding sediments. The largest increase in sensitivity was achieved in low-grade Ta tumors, with 82 out of 98 cases positive in the filter samples (84%) versus 74 out of 98 in the sediments (75%). Our results show that pre-analytic processing of voided urine by size-based filtration can increase the sensitivity for DNA-based detection of bladder cancer.